tetano
Editor, Senior Moderator
PLoS Comput Biol
. 2022 Jul 28;18(7):e1010343.
doi: 10.1371/journal.pcbi.1010343. Online ahead of print.
Binding mechanism of oseltamivir and influenza neuraminidase suggests perspectives for the design of new anti-influenza drugs
Jiaye Tao[SUP] 1 [/SUP], Heping Wang[SUP] 2 [/SUP], Wenjian Wang[SUP] 2 [/SUP], Na Mi[SUP] 1 [/SUP], Wei Zhang[SUP] 1 [/SUP], Qiujia Wen[SUP] 1 [/SUP], Jiajing Ouyang[SUP] 1 [/SUP], Xinyun Liang[SUP] 1 [/SUP], Min Chen[SUP] 1 [/SUP], Wentao Guo[SUP] 1 [/SUP], Guoming Li[SUP] 1 [/SUP], Jun Liu[SUP] 1 [/SUP], Hanning Zhao[SUP] 1 [/SUP], Xin Wang[SUP] 1 [/SUP], Xuemeng Li[SUP] 1 [/SUP], Shengjun Feng[SUP] 1 [/SUP], Xinguang Liu[SUP] 3 [/SUP], Zhiwei He[SUP] 4 [/SUP], Zuguo Zhao[SUP] 1 [/SUP]
Affiliations
Abstract
Oseltamivir is a widely used influenza virus neuraminidase (NA) inhibitor that prevents the release of new virus particles from host cells. However, oseltamivir-resistant strains have emerged, but effective drugs against them have not yet been developed. Elucidating the binding mechanisms between NA and oseltamivir may provide valuable information for the design of new drugs against NA mutants resistant to oseltamivir. Here, we conducted large-scale (353.4 μs) free-binding molecular dynamics simulations, together with a Markov State Model and an importance-sampling algorithm, to reveal the binding process of oseltamivir and NA. Ten metastable states and five major binding pathways were identified that validated and complemented previously discovered binding pathways, including the hypothesis that oseltamivir can be transferred from the secondary sialic acid binding site to the catalytic site. The discovery of multiple new metastable states, especially the stable bound state containing a water-mediated hydrogen bond between Arg118 and oseltamivir, may provide new insights into the improvement of NA inhibitors. We anticipated the findings presented here will facilitate the development of drugs capable of combating NA mutations.
. 2022 Jul 28;18(7):e1010343.
doi: 10.1371/journal.pcbi.1010343. Online ahead of print.
Binding mechanism of oseltamivir and influenza neuraminidase suggests perspectives for the design of new anti-influenza drugs
Jiaye Tao[SUP] 1 [/SUP], Heping Wang[SUP] 2 [/SUP], Wenjian Wang[SUP] 2 [/SUP], Na Mi[SUP] 1 [/SUP], Wei Zhang[SUP] 1 [/SUP], Qiujia Wen[SUP] 1 [/SUP], Jiajing Ouyang[SUP] 1 [/SUP], Xinyun Liang[SUP] 1 [/SUP], Min Chen[SUP] 1 [/SUP], Wentao Guo[SUP] 1 [/SUP], Guoming Li[SUP] 1 [/SUP], Jun Liu[SUP] 1 [/SUP], Hanning Zhao[SUP] 1 [/SUP], Xin Wang[SUP] 1 [/SUP], Xuemeng Li[SUP] 1 [/SUP], Shengjun Feng[SUP] 1 [/SUP], Xinguang Liu[SUP] 3 [/SUP], Zhiwei He[SUP] 4 [/SUP], Zuguo Zhao[SUP] 1 [/SUP]
Affiliations
- PMID: 35901128
- DOI: 10.1371/journal.pcbi.1010343
Abstract
Oseltamivir is a widely used influenza virus neuraminidase (NA) inhibitor that prevents the release of new virus particles from host cells. However, oseltamivir-resistant strains have emerged, but effective drugs against them have not yet been developed. Elucidating the binding mechanisms between NA and oseltamivir may provide valuable information for the design of new drugs against NA mutants resistant to oseltamivir. Here, we conducted large-scale (353.4 μs) free-binding molecular dynamics simulations, together with a Markov State Model and an importance-sampling algorithm, to reveal the binding process of oseltamivir and NA. Ten metastable states and five major binding pathways were identified that validated and complemented previously discovered binding pathways, including the hypothesis that oseltamivir can be transferred from the secondary sialic acid binding site to the catalytic site. The discovery of multiple new metastable states, especially the stable bound state containing a water-mediated hydrogen bond between Arg118 and oseltamivir, may provide new insights into the improvement of NA inhibitors. We anticipated the findings presented here will facilitate the development of drugs capable of combating NA mutations.